Depression is increasingly recognized as an independent prognostic risk factor in patients with coronary artery disease and coronary artery bypass grafting (CABG). The use of selective serotonin reuptake inhibitors (SSRIs) for depression in patients with cardiac disease is becoming more prevalent. We examined the long-term outcomes of patients on SSRIs before CABG. We prospectively examined collected data in the Duke Databank for Cardiovascular Disease from January 1, 1999 to December 31, 2003. The median and maximum follow-up periods were 3 and 6 years, respectively. We screened patients who underwent CABG (n = 5,364) and excluded those who underwent simultaneous CABG and valvular surgery (n = 570). SSRI antidepressants included fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, venlafaxine, and clomipramine, and their use was determined from the inpatient pharmacy records during the index hospitalization. Outcomes included event-free survival from all-cause mortality, rehospitalization, and a composite end point of all-cause mortality or rehospitalization. Of 4,794 CABG-only patients, 246 (5.1%) took SSRIs before CABG. The SSRI group had a higher prevalence of diabetes, hypercholesterolemia, hypertension, cerebrovascular disease, peripheral vascular disease, and previous cardiovascular intervention. After adjustment for baseline differences, patients on SSRIs before CABG had increased risks of mortality, rehospitalization, and the composite end point (hazard ratio 1.61, 95% confidence interval 1.17 to 2.21, p = 0.003; hazard ratio 1.52, 95% confidence interval 1.30 to 1.77, p <0.0001; and hazard ratio 1.46, 95% confidence interval 1.26 to 1.70, p <0.0001, respectively). In conclusion, SSRI use before CABG was associated with a higher risk of long-term post-CABG mortality and rehospitalization. The explanation behind these findings requires further research.